Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders

ABSTRACT

The invention relates to a pharmaceutical combined preparation of LHRH analogues and anti-oestrogens having tissue-selective oestrogen activity and also to its use for the treatment of gynaecological disorders, especially for the treatment of endometrioses and myomas.

[0001] The invention relates to a pharmaceutical combined preparation ofLHRH analogues and anti-oestrogens having a tissue-selective oestrogenicactivity, and also to its use for the treatment of gynaecologicaldisorders, especially for the treatment of endometrioses and myomas.

[0002] Gynaecological disorders and diseases considerably reduce thequality of life of women and frequently result, in some cases inaddition to unbearable pain, in infertility. One of the most commondiseases in women of child-bearing age (5% to 10%) is endometriosis.Associated-with it are severe pain during menstruation and a limitedfertility rate to sterility. In the case of the myoma, a benign tumourin the muscle tissue of the uterus, the incidence is high too (in 10 to25% of women in their 30s) . Myomas may cause heavy abnormal menstrualbleeding (hypermenorrhoea), painful menstruation (dysmenorrhoea) and/orintermenstrual bleeding (metrorrhagia, menorrhagia) and each, dependingon the condition, may also result in limited fertility. In addition todysmenorrhoea caused by endometriosis and by myomas, dysmenorrhoea thatis caused by functional disorders (by hormonal and vegetative disorders)also occurs.

[0003] The gonal steroids (oestrogens, gestagens), which are under thecontrol of the hypothalamic-pituitary system, and growth factors(including also cytokines) play a decisive role in the clinicalsyndromes described. Treatment of such diseases and disorders is usuallyeffected with hormones, such as LHRH analogues (Lemay, A. et al.,Fertil. Steril., 41, 863-871 (1984)). In some women, however, these arenot tolerated without side effects. For example, it is known thattreatment with LHRH agonists may result in side effects such as, forexample, hypo-oestrogenaemia (risk of osteoporosis) (Dawood, M. Y. etal., Fertil. Steril. 52, 21-25, (1989)) and treatment with danazol mayresult in androgenisation phenomena (Dmowski, W. P. et al., Am. J.Obstet. Gynecol., 130, 41-48 (1978)).

[0004] No established and proven long-term medicament treatment hasexisted hitherto for myomas. The medicament treatment currently used isassociated with distinct side effects. For example, the use of LHRMagonists for more than six months results in a hypo-oestrogenic state inwomen (Matta, W. H. et al., Br. Med. J., 294, 1523-1525, (1987)) and,associated with that, a reduction in bone density, which increases therisk of osteoporosis (Dawood, M. Y. Int. J. Gynecol. Obstet., 40, 29-42(1993)). Other side effects associated with oestrogen withdrawal (hotflushes) are also described by Dawood.

[0005] Studies for the treatment of gynaecological disorders with LHRHanalogues and oestrogens—so-called Add-Back or HRT treatment regimes—areknown for the purpose of avoiding those side effects. The discovery ofan oestrogen dose that completely prevents a reduction in bone densityusing LHRH agonist therapy (Howell, R. et al., Fertil, Steril. 64,474-481, (1995)) without at the same time stimulating endometriosis orstimulating the endometrium, which may result in endometrium hyperplasiaand, associated with that, endometrium carcinomas, has hitherto beenunsuccessful, however.

[0006] The problem underlying the invention is therefore to prepare apharmaceutical combined preparation for the treatment of gynaecologicaldisorders, especially for the treatment of endometrioses and myomas,with which a reduction in bone density is prevented and thedisadvantages of previous hormone treatments are avoided.

[0007] The problem is solved in accordance with the invention by apharmaceutical combined preparation that comprises two activeingredients, the first of which is an LHRH analogue or a combination ofLHRH analogues and the second of which is an anti-oestrogen havingtissue-selective oestrogenic activity.

[0008] The LHRH analogue is an LHRH agonist or antagonist.

[0009] Any LHRH antagonist or LHRH agonist may be used within the scopeof the invention. Preferred LHRH analogues are selected from the groupof compounds Leuprorelin, Cetrorelix, Antide, Buserelin, Ramorelix,Zoladex,2-(4-acetylaminophenyl)-4,7-dihydro-7-(2-methoxybenzyl)-3-(N-methyl-N-benzylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylicacid ethyl ester and5-benzoyl-7-(2,6-difluorobenzyl)-4,7-dihydro-3-(N-methyl-N-benzylamino-methyl)-2-(4-propionylamidophenyl)-4-oxothieno[2,3-b]pyridine.

[0010] The active ingredients are generally in separate forms ofadministration or, in the case of orally bioavailable LHRH antagonists,also in a joint form of administration.

[0011] The LHRH analogues preferably used are known and are described inthe patent specifications U.S. Pat. No. 4,005,063 (Leuprorelin), EP-B10299 402 (Cetrorelix), GB 1 523 623 (Buserelin), EP-A 0 451 791(Ramorelix), WO-A 89/01944 (Antide), WO-A 92/20711(Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys(Mor)-D-Ala-NH₂), U.S. Pat.No. 4,100,274 (Zoladex) and WO-A 95/28405(2-(4-acetylaminophenyl)-4,7-dihydro-7-(2-methoxybenzyl)-3-(N-methyl-N-benzylaminomethyl)-4-oxothieno[2,3-b]pyridine-5-carboxylicacid ethyl ester).

[0012] They are prepared and packaged according to processes known perse and, depending on the desired use, are available in oral or nasalform, in the form of an injection, or in the form of a long-termpreparation to be administered topically or intravaginally. According tothe invention, the LHRH analogues may be administered as individualdoses or as depot forms.

[0013] A unit dose contains different amounts of active ingredientdepending in each case on the form of administration. For example, inthe case of oral administration usually from 2 μg to 20 mg of LERHanalogue is administered per kg of body weight. The administration maybe in solid or liquid form. For intravenous, subcutaneous,intramuscular, intranasal or intravaginal administration, the amounts ofLHRH analogues are from 0.02 μg to 2.5 mg per kg of body weight. Forparenteral administration there is preferably used an isotonic sodiumchloride or dextrose solution that optionally is adjusted with a bufferto a pH value of from 5 to 9, preferably to the pH value of the blood.

[0014] Leuprorelin is preferably used orally at a dose of from 2 to 100μg/kg of body weight (daily dose); one tablet contains preferably from0.1 to 5.0 mg of Leuprorelin. The dose for parenteral administration ispreferably from 0.02 to 1.0 μg/kg of body weight.

[0015] Cetrorelix is used preferably in the form of a physiologicalsaline with an amount of active ingredient of from 0.1 to 2.5 mg/kg ofbody weight. In DE 43 42 092, also slow-release formulations ofCetrorelix are described.

[0016] Buserelin is administered preferably in the following doses:

[0017] from 0.02 to 1 μg/kg of body weight (intravenous),

[0018] from 0.02 to 2 μg/kg of body weight (subcutaneous),

[0019] from 0.02 to 10 μg/kg of body weight (intramuscular),

[0020] from 0.1 to 50 μg/kg of body weight (intranasal) and

[0021] from 10 to 200 μg/kg of body weight (oral).

[0022] As in the case of Cetrorelix, slow-release formulations are alsopossible. In the case of an implant, the implant contains from 1 to 6 mgof Cetrorelix.

[0023] Zoladex is preferably administered orally with a content of from50 μg to 20 mg/kg of body weight and parenterally with a content of from0.02 μg to 100 μg/kg of body weight or using a slow-release system (WO-A93/24150).

[0024] Antide is, like Cetrorelix, administered in an amount of from 0.1to 2.5 mg/kg of body weight.

[0025] The administration of Ramorelix is carried out preferably inliposomal form.

[0026] Depot formulations for peptides (microparticles, implants) aredescribed inter alia in EP 0 505 966 and EP 0 315 875.

[0027] According to the invention, the second active ingredientcomponent of the combined preparation is an antioestrogen havingtissue-selective oestrogenic activity.

[0028] Anti-oestrogenic substances are used inter alia in tumourtherapy.

[0029] Within the scope of the invention there are to be understood byanti-oestrogens having tissue-selective oestrogenic activity so-calledSERMs (selective oestrogen-receptor modulators) which exert theirpartial agonistic oestrogenic activity tissue- and organ-selectively.

[0030] Any antioestrogen having tissue-selective oestrogenic activitymay be used in accordance with the invention. Preferably used are thoseselected from the group Raloxifen, Droloxifen, Centchroman andderivatives thereof. Anti-oestrogens of the Raloxifen type areespecially preferred.

[0031] The anti-oestrogens mentioned are known. For example Raloxifen is6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene.In combination with parathyroid hormone, Raloxifen and its derivativesare used to increase bone mass (EP 0 635 270).

[0032] The active ingredient content of the anti-oestrogen used inaccordance with the invention is in the case of daily administrationfrom 0.1 μg to 10 mg of antioestrogen per kg of body weight, dependingon the form of administration. The anti-oestrogens may be administeredintravenously, subcutaneously, intramuscularly, orally, intranasally orintravaginally. Slow-release formulations are also possible, in whichcase the amount released daily lies also within the above-mentionedrange.

[0033] The administration of the LHRH analogue and of the anti-oestrogento the patient may be simultaneous and/or chronologically sequential.Various treatment regimes are possible

[0034] 1. The LHRH analogue is administered simultaneously with thetissue-selective anti-oestrogen over the same period of time.Administration is possible daily, every three days, weekly or oncemonthly over a period of from 1 to 6 months. Longer administration isalso readily possible. In the case of monthly administration a depotformulation is preferred.

[0035] 2. The LHRH analogue is first of all administered simultaneouslywith the tissue-selective anti-oestrogen over a particular period oftime. The information given in 1 applies in respect of period andfrequency of administration (daily or at greater intervals). Treatmentis then continued with the anti-oestrogen only. Here, too, theinformation given in 1 applies in respect of period and frequency ofadministration.

[0036] 3. The treatment with the LHRH analogue is conducted over aparticular period of time and terminated. Following this thetissue-selective anti-oestrogen is then administered. For eachcomponent, the period and frequency of administration may be selected asindicated in 1.

[0037] It was established that the treatment with the combinedpreparation according to the invention surprisingly prevents thehitherto observed LHRH analogue-induced reduction in bone density, andthe endometriosis, inhibited in its growth, is not stimulated again, andthe growth of the normal endometrium in the uterus also is notstimulated.

[0038] The pharmaceutical combined preparation according to theinvention is suitable especially for long-term treatment ofendometrioses and myomas and other steroid(sex)-hormone-dependentdisorders, since on the one hand the side effects that normally occurwith an LHRH analogue (agonist or antagonist) treatment are avoided andon the other hand lost bone mass is rebuilt (for example in the case ofadministration of the tissue-selective anti-oestrogen after completionof an LHRR analogue treatment). At the same time the growth inhibitionof the endometriosis is maintained without the endometrium in the uterusbeing stimulated.

[0039] Variant 1 has proved especially preferred for long-term therapy.

[0040] The pharmaceutical combined preparation according to theinvention is prepared, for example, by formulating the LHRH analoguesand the anti-oestrogens having tissue-selective oestrogenic activityseparately from one another with the customary pharmaceutical carriers,excipients and/or additives; the forms of administration of theindividual active ingredients do not have to be identical. It is whollypossible, for example, for one active ingredient of the combinedpreparation to be administered orally while the other active ingredientis administered subcutaneously or nasally.

[0041] In the case of orally bioavailable LHRH analogues, it is alsopossible for the two active ingredients (LHRH analogues plusanti-oestrogen) to be formulated together for oral administration.Separate oral forms of administration are also possible.

[0042] The invention relates also to a packaging unit which, in the caseof peptidergic LHRH analogues, comprises at least three components. Theunit contains two spatially separately packaged active ingredients, oneof which is an LHRH analogue or a combination of LHRH analogues, and theother of which is an anti-oestrogen having tissue-selective oestrogenicactivity. The third component is an information leaflet for thesimultaneous and/or chronologically sequential administration of theforms of administration.

[0043] The invention relates also to the use of an LHRH analogue or acombination of LHRH analogues and an anti-oestrogen havingtissue-selective oestrogenic activity for the treatment ofgynaecological disorders, especially for the treatment of endometriosesand myomas.

[0044] The invention is illustrated further in the following by Exampleswithout, however, being limited to those Examples.

EMBODIMENTS EXAMPLES Example 1

[0045] Effect of LHRH Administration and Raloxifen Administration onExperimentally Produced Endometriosis in the Rat

[0046] 1.1 Comparison of the Administration of Each of the ActiveIngredient Components Alone with the Simultaneous Administration of theActive Ingredients (Combined Preparation)

[0047] Method

[0048] Fragments of endometrium were transplanted into different regionsof the abdominal cavity of 60 animals.

[0049] Four weeks later the development of the endometriosis (cysticendometriosis foci) was examined.

[0050] The animals were then treated for 4 weeks with the LHRHantagonists Antide (0.5 mg/animal every 3 days s.c.) and Raloxifen (3mg/animal per day p.o.) in each case alone, or in a combination of thetwo compounds. At the end the size of the endometriosis foci before thebeginning of the treatment was compared with the values after 4 weeks'treatment.

[0051] The combination of LHR antagonist plus Raloxifen resulted in acomplete regression of the endometriosis without there being asignificant reduction in bone mass. At the same time no oestrogeniceffects on the uterus (no stimulation of the endometrium) were observed.

[0052] By comparison, although treatment with the LHRH antagonists aloneresulted in a complete regression of the endometriosis foci, at the sametime it caused a reduction in endogenous oestrogen levels correspondingto an ovariectomy. The result was a distinct reduction in bone densityand an increase in osteoclast activity.

[0053] Administration of Raloxifen alone resulted in a partialregression of the endometriosis.

[0054] 1.2. LHRH Antagonist Antide and Raloxifen for Simultaneous andChronologically Sequential Administration

[0055] 60 animals received the LHRH antagonist Antide and Raloxifen inparallel for the first 2 weeks and Raloxifen alone for the following 2weeks. The doses were selected as in 1.1.

[0056] As with the simultaneous administration of the activeingredients, the result to be recorded was a complete regression of theendometriosis without a significant reduction in bone mass. At the sametime there were no oestrogenic effects on the uterus.

[0057] 1.3. Chronologically Sequential Administration of the CombinedPreparation

[0058] 60 animals received the LHRH antagonist Antide for 2 weeks. Oncompletion of the LHRH administration Raloxifen was then administeredfor 2 weeks.

[0059] This sequential treatment also resulted in 100% regression of theendometriosis without a reduction in bone density.

Example 2

[0060] Analogously to Example 1, treatment with LHRH antagonistsAc-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys(Mor)-D-Ala-NH₂ and Droloxifenwas carried out on 40 animals.

[0061] The same results could be achieved as in Example 1.

1. Pharmaceutical combined preparation comprising two active ingredientsone of which is an LHRH analogue or a combination of LHRH analogues andthe other of which is an anti-oestrogen having tissue-selectiveoestrogenic activity.
 2. Combined preparation according to claim 1,characterised in that the LHRH analogue is an LHRH agonist or an LHRHantagonist.
 3. Combined preparation according to claim 1 or 2,characterised in that the LERH analogue is selected from the group ofcompounds Leuprorelin, Cetrorelix, Buserelin, Antide,Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Cit-Leu-Lys(Mor)-D-Ala-NH₂, Ramorelix,Zoladex and derivatives thereof.
 4. Combined preparation according toany one of claims 1 to 3, characterised in that the LHRH analogue or thecombination of LHRH analogues is orally bioavailable.
 5. Combinedpreparation according to any one of claims 1 to 4, characterised in thatthe LHRH analogue is a non-peptidergic LHRH agonist or antagonist. 6.Combined preparation according to any one of claims 1 to 5,characterised in that the anti-oestrogen is selected from the group ofcompounds Raloxifen, Droloxifen, Centchroman and derivatives thereof. 7.Combined preparation according to any one of claims 1 to 6,characterised in that the anti-oestrogen is of the Raloxifen type. 8.Combined preparation according to any one of claims 1 to 7,characterised in that the two active ingredients are in separate formsof administration.
 9. Combined preparation according to any one ofclaims 1 to 7, characterised in that the two active ingredients are injoint forms of administration.
 10. Process for the manufacture of apharmaceutical combined preparation, characterised in that an LHRHanalogue or a combination of LHRH analogues and an anti-oestrogen havingtissue-selective activity are formulated with customary pharmaceuticalcarriers, excipients and/or additives, separately from one another ortogether.
 11. Process according to claim 10, characterised in that theLHRH analogue or the combination of LHRH analogues and theanti-oestrogen having tissue-selective activity are formulatedseparately from one another.
 12. Process according to claim 10,characterised in that the LHRH analogue or the combination of LHRHanalogues and the anti-oestrogen having tissue-selective activity areformulated together.
 13. The use of an LHRH analogue or a combination ofLHRH analogues, and of an anti-oestrogen having tissue-selectiveoestrogenic activity, for the treatment of gynaecological disorders,especially for the treatment of endometrioses and myomas.
 14. Useaccording to claim 13, characterised in that LHRH analogue andanti-oestrogen are administered simultaneously and/or in chronologicalsequence.
 15. Packaging unit comprising two spatially separatelypackaged active ingredients, one of which is an LHRH analogue or acombination of LHRH analogues and the other of which is ananti-oestrogen having tissue-selective oestrogenic activity, andcomprising as third component an information leaflet on the simultaneousand/or chronologically sequential administration of the forms ofadministration.